The present invention relates to the prevention, treatment and amelioration of neurodegenerative or Alzheimer's disease, and more particularly to the prevention, treatment and amelioration of Alzheimer's disease with new donepezil like compounds which act as inhibitors of central cholinesterase enzyme following the indirect cholinomimetic pathway.
Alzheimer's disease (AD) is a progressive and neurodegenerative disease in the brain characterized by abnormal clumps and tangled bundles of fibers composed of misplaced proteins. Age is the most important factor for AD since the number of people afflicted with the disease doubles every 5 years in those over 65 years old. Symptoms of AD include memory loss, language deterioration and impaired ability to memory loss, language deterioration, and impaired ability to mentally manipulate visual information, poor judgment, confusion, restlessness, and mood swings. Eventually AD destroys cognition, personality, and the ability to function. The early symptoms of AD, which include forgetfulness and loss of concentration, are often missed because they resemble natural signs of aging.
Acetylcholine is involved in sending many types of messages throughout the brain, including those involving memory and learning. It carries a message once released into the synapse of a neuron towards a specific sites located on the next neuron. This message is sent until another enzyme (acetylcholinesterase, AChE) enters the synapse to break down acetylcholine. Damages to the cholinergic system in the brain, i.e. a decrease in the choline acetyltransferase activity, has been suggested to play a role in the memory losses that are associated with AD. Therefore, it has been established that the inhibition of AChE allows preventing a too early break down of the few amount of acetylcholine that is still formed in the patients afflicted with AD.
The patent application WO 97/08146 discloses a series of carbamates based on the structure of pyridostigmine as potential drugs for the treatment of cognitive impairments associated with cholinergic perturbances such as in AD. However the document is directed to compounds which differ from that of the present invention and have the drawback of being unstable and of being rapidly deactivated.
Similarly, Wuest et al (JACS Vol. 73, 1951 pp 1210-1216) discloses positively charged pyridine carbamates; Wang et al. (Nuclear Medicine and Biology 31 (2004)), discloses pyridostigmine, edrophonium and neostigmine agents as AChE. However none of the reported compounds have the same structure as the compounds of the instant invention and these are deprived of the withdrawing electron group attached to the ring.
In fact there are only few acetylcholinesterase inhibitors (AChEi) that have been useful in the treatment of neurodegenerative diseases. For example, donepezil, tacrine, rivastigmine and galantamine are indicated. Donepezil, also known as 1-benzyl-4-(5,6-dimethoxy-1-oxoindan-2-ylmethyl)piperidine, is disclosed in the European patent EP 296 560. EP 296 560 describes 1,4-substituted piperidines and several structures derived from indanyl or indanonyl among others, and linked to the piperidine through a organic group X having lots of significations, including carbamoyl groups, carbamates, esters. Said compounds are active against CNS diseases. However, nowhere are described compounds having an unsaturated nitrogen containing-heterocycle such as pyridine or dihydropyridine.
However, the manifestation of peripheral activity in the course of the treatment causes serious adverse effects on peripheral organs, which limits the therapeutic potential of these cholinesterase inhibitors. In addition, it is known that these drugs loose their therapeutical efficacy with time which requires increased daily dosages with the associated side effects.
There is thus a need for new cholinesterase inhibitors agent which could act against neurodegenerative diseases having a higher affinity for inhibiting central AChE instead of peripheral AChE. These agents should also be able to cross the Blood Brain Barrier (BBB) which protects the brain from harmful substances in the blood stream, while at the same time supplying the brain with the required nutrients for proper function. The BBB strictly limits passages to the brain through both physical and metabolic barriers and is often the rate limiting factor in determining permeation of therapeutic drugs into the brain.
Patent application WO 2006/103120 provides prodrugs which appeared to be particularly efficient in the treatment of neurodegenerative diseases. In their oxidizable and non protonable (neutral nitrogen) forms, the prodrugs are deprived of activity against central or peripheral acetylcholinesterase but have the ability to easily pass through the blood brain barrier into the central nervous system (CNS) where they become active upon oxidation. These prodrugs have the further advantage of being entrapped into the CNS once in their oxidized form, which avoids any side effect into the peripherical nervous system (PNS). After having completed their anticholinesterase activity, the molecules are inactivated and degraded in situ, which allows their degradation. Nevertheless, the document focuses on carbamate prodrugs and thus differs from the compounds of the instant invention.
The patent application WO 99/36405 discloses quaternary salts of donezepil derivatives which are however different from the compounds within the scope of the invention since they do not comprise an electronic withdrawing group on the pyridine moiety. In addition, this application is concerned with the use of quaternary salts as intermediate materials in the synthesis of donezepil to afford improved yields rather than on their therapeutical use.